[Script Info]
Title: 
[Events]
Format: Layer, Start, End, Style, Name, MarginL, MarginR, MarginV, Effect, Text
Dialogue: 0,0:00:01.06,0:00:04.08,Default,,0000,0000,0000,,This is a tuberculosis ward,
Dialogue: 0,0:00:04.10,0:00:07.92,Default,,0000,0000,0000,,and at the time this picture was taken\Nin the late 1800s,
Dialogue: 0,0:00:07.94,0:00:10.56,Default,,0000,0000,0000,,one in seven of all people
Dialogue: 0,0:00:10.58,0:00:12.34,Default,,0000,0000,0000,,died from tuberculosis.
Dialogue: 0,0:00:12.78,0:00:15.54,Default,,0000,0000,0000,,We had no idea\Nwhat was causing this disease.
Dialogue: 0,0:00:16.14,0:00:18.20,Default,,0000,0000,0000,,The hypothesis was actually
Dialogue: 0,0:00:18.22,0:00:21.48,Default,,0000,0000,0000,,it was your constitution\Nthat made you susceptible.
Dialogue: 0,0:00:21.50,0:00:24.24,Default,,0000,0000,0000,,And it was a highly romanticized disease.
Dialogue: 0,0:00:24.26,0:00:27.08,Default,,0000,0000,0000,,It was also called consumption,
Dialogue: 0,0:00:27.10,0:00:30.24,Default,,0000,0000,0000,,and it was the disorder of poets
Dialogue: 0,0:00:30.26,0:00:32.100,Default,,0000,0000,0000,,and artists and intellectuals.
Dialogue: 0,0:00:33.02,0:00:36.76,Default,,0000,0000,0000,,And some people actually thought\Nit gave you heightened sensitivity
Dialogue: 0,0:00:36.78,0:00:38.98,Default,,0000,0000,0000,,and conferred creative genius.
Dialogue: 0,0:00:40.70,0:00:42.84,Default,,0000,0000,0000,,By the 1950s,
Dialogue: 0,0:00:42.86,0:00:45.44,Default,,0000,0000,0000,,we instead knew\Nthat tuberculosis was caused
Dialogue: 0,0:00:45.46,0:00:48.84,Default,,0000,0000,0000,,by a highly contagious\Nbacterial infection,
Dialogue: 0,0:00:48.86,0:00:51.04,Default,,0000,0000,0000,,which is slightly less romantic,
Dialogue: 0,0:00:51.06,0:00:53.32,Default,,0000,0000,0000,,but that had the upside
Dialogue: 0,0:00:53.34,0:00:56.68,Default,,0000,0000,0000,,of us being able to maybe\Ndevelop drugs to treat it.
Dialogue: 0,0:00:56.70,0:00:59.72,Default,,0000,0000,0000,,So doctors had discovered\Na new drug, iproniazid,
Dialogue: 0,0:00:59.74,0:01:03.12,Default,,0000,0000,0000,,that they were optimistic\Nmight cure tuberculosis,
Dialogue: 0,0:01:03.14,0:01:04.92,Default,,0000,0000,0000,,and they gave it to patients,
Dialogue: 0,0:01:04.94,0:01:06.72,Default,,0000,0000,0000,,and patients were elated.
Dialogue: 0,0:01:06.74,0:01:10.24,Default,,0000,0000,0000,,They were more social, more energetic.
Dialogue: 0,0:01:10.26,0:01:14.86,Default,,0000,0000,0000,,One medical report actually says\Nthey were "dancing in the halls."
Dialogue: 0,0:01:15.50,0:01:17.12,Default,,0000,0000,0000,,And unfortunately,
Dialogue: 0,0:01:17.14,0:01:19.86,Default,,0000,0000,0000,,this was not necessarily\Nbecause they were getting better.
Dialogue: 0,0:01:20.42,0:01:22.62,Default,,0000,0000,0000,,A lot of them were still dying.
Dialogue: 0,0:01:23.66,0:01:30.26,Default,,0000,0000,0000,,Another medical report describes them\Nas being "inappropriately happy."
Dialogue: 0,0:01:31.22,0:01:34.82,Default,,0000,0000,0000,,And that is how the first\Nantidepressant was discovered.
Dialogue: 0,0:01:35.98,0:01:40.04,Default,,0000,0000,0000,,So accidental discovery\Nis not uncommon in science,
Dialogue: 0,0:01:40.06,0:01:43.20,Default,,0000,0000,0000,,but it requires more\Nthan just a happy accident.
Dialogue: 0,0:01:43.22,0:01:46.66,Default,,0000,0000,0000,,You have to be able to recognize it\Nfor discovery to occur.
Dialogue: 0,0:01:47.50,0:01:50.24,Default,,0000,0000,0000,,As a neuroscientist,\NI'm going to talk to you a little bit
Dialogue: 0,0:01:50.26,0:01:51.68,Default,,0000,0000,0000,,about my firsthand experience
Dialogue: 0,0:01:51.70,0:01:54.92,Default,,0000,0000,0000,,with whatever you want to call\Nthe opposite of dumb luck --
Dialogue: 0,0:01:54.94,0:01:56.56,Default,,0000,0000,0000,,let's call it smart luck.
Dialogue: 0,0:01:56.58,0:01:59.30,Default,,0000,0000,0000,,But first, a bit more background.
Dialogue: 0,0:02:00.46,0:02:03.12,Default,,0000,0000,0000,,Thankfully, since the 1950s,
Dialogue: 0,0:02:03.14,0:02:07.12,Default,,0000,0000,0000,,we've developed some other drugs\Nand we can actually now cure tuberculosis.
Dialogue: 0,0:02:07.14,0:02:10.80,Default,,0000,0000,0000,,And at least in the United States,\Nthough not necessarily in other countries,
Dialogue: 0,0:02:10.82,0:02:12.32,Default,,0000,0000,0000,,we have closed our sanitoriums
Dialogue: 0,0:02:12.34,0:02:16.02,Default,,0000,0000,0000,,and probably most of you\Nare not too worried about TB.
Dialogue: 0,0:02:16.90,0:02:19.56,Default,,0000,0000,0000,,But a lot of what was true\Nin the early 1900s
Dialogue: 0,0:02:19.58,0:02:21.44,Default,,0000,0000,0000,,about infectious disease,
Dialogue: 0,0:02:21.46,0:02:24.10,Default,,0000,0000,0000,,we can say now\Nabout psychiatric disorders.
Dialogue: 0,0:02:24.82,0:02:27.84,Default,,0000,0000,0000,,We are in the middle\Nof an epidemic of mood disorders
Dialogue: 0,0:02:27.86,0:02:31.62,Default,,0000,0000,0000,,like depression and post-traumatic\Nstress disorder, or PTSD.
Dialogue: 0,0:02:32.30,0:02:36.16,Default,,0000,0000,0000,,One in four of all adults\Nin the United States
Dialogue: 0,0:02:36.18,0:02:37.66,Default,,0000,0000,0000,,suffers from mental illness,
Dialogue: 0,0:02:38.18,0:02:41.32,Default,,0000,0000,0000,,which means that if you haven't\Nexperienced it personally
Dialogue: 0,0:02:41.34,0:02:43.64,Default,,0000,0000,0000,,or someone in your family hasn't,
Dialogue: 0,0:02:43.66,0:02:46.92,Default,,0000,0000,0000,,it's still very likely\Nthat someone you know has,
Dialogue: 0,0:02:46.94,0:02:48.58,Default,,0000,0000,0000,,though they may not talk about it.
Dialogue: 0,0:02:50.22,0:02:53.52,Default,,0000,0000,0000,,Depression has actually now surpassed
Dialogue: 0,0:02:53.54,0:02:58.40,Default,,0000,0000,0000,,HIV/AIDS, malaria, diabetes and war
Dialogue: 0,0:02:58.42,0:03:01.68,Default,,0000,0000,0000,,as the leading cause\Nof disability worldwide.
Dialogue: 0,0:03:01.70,0:03:05.32,Default,,0000,0000,0000,,And also, like tuberculosis in the 1950s,
Dialogue: 0,0:03:05.34,0:03:07.40,Default,,0000,0000,0000,,we don't know what causes it.
Dialogue: 0,0:03:07.42,0:03:09.36,Default,,0000,0000,0000,,Once it's developed, it's chronic,
Dialogue: 0,0:03:09.38,0:03:10.88,Default,,0000,0000,0000,,lasts a lifetime,
Dialogue: 0,0:03:10.90,0:03:13.22,Default,,0000,0000,0000,,and there are no known cures.
Dialogue: 0,0:03:14.66,0:03:16.88,Default,,0000,0000,0000,,The second antidepressant we discovered,
Dialogue: 0,0:03:16.90,0:03:19.36,Default,,0000,0000,0000,,also by accident, in the 1950s,
Dialogue: 0,0:03:19.38,0:03:22.58,Default,,0000,0000,0000,,from an antihistamine\Nthat was making people manic,
Dialogue: 0,0:03:23.86,0:03:25.06,Default,,0000,0000,0000,,imipramine.
Dialogue: 0,0:03:26.22,0:03:29.88,Default,,0000,0000,0000,,And in both the case of the tuberculosis\Nward and the antihistamine,
Dialogue: 0,0:03:29.90,0:03:31.60,Default,,0000,0000,0000,,someone had to be able to recognize
Dialogue: 0,0:03:31.62,0:03:34.04,Default,,0000,0000,0000,,that a drug that was designed\Nto do one thing --
Dialogue: 0,0:03:34.06,0:03:36.64,Default,,0000,0000,0000,,treat tuberculosis\Nor suppress allergies --
Dialogue: 0,0:03:36.66,0:03:39.40,Default,,0000,0000,0000,,could be used to do\Nsomething very different --
Dialogue: 0,0:03:39.42,0:03:40.62,Default,,0000,0000,0000,,treat depression.
Dialogue: 0,0:03:41.38,0:03:44.40,Default,,0000,0000,0000,,And this sort of repurposing\Nis actually quite challenging.
Dialogue: 0,0:03:44.42,0:03:48.36,Default,,0000,0000,0000,,When doctors first saw\Nthis mood-enhancing effect of iproniazid,
Dialogue: 0,0:03:48.38,0:03:50.84,Default,,0000,0000,0000,,they didn't really recognize\Nwhat they saw.
Dialogue: 0,0:03:50.86,0:03:52.72,Default,,0000,0000,0000,,They were so used to thinking about it
Dialogue: 0,0:03:52.74,0:03:55.52,Default,,0000,0000,0000,,from the framework\Nof being a tuberculosis drug
Dialogue: 0,0:03:55.54,0:03:57.60,Default,,0000,0000,0000,,that they actually just listed it
Dialogue: 0,0:03:57.62,0:04:00.40,Default,,0000,0000,0000,,as a side effect, an adverse side effect.
Dialogue: 0,0:04:00.42,0:04:01.57,Default,,0000,0000,0000,,As you can see here,
Dialogue: 0,0:04:01.60,0:04:05.62,Default,,0000,0000,0000,,a lot of these patients in 1954\Nare experiencing severe euphoria.
Dialogue: 0,0:04:06.90,0:04:10.52,Default,,0000,0000,0000,,And they were worried\Nthat this might somehow interfere
Dialogue: 0,0:04:10.54,0:04:13.40,Default,,0000,0000,0000,,with their recovering from tuberculosis.
Dialogue: 0,0:04:13.42,0:04:19.68,Default,,0000,0000,0000,,So they recommended that iproniazid\Nonly be used in cases of extreme TB
Dialogue: 0,0:04:19.70,0:04:23.38,Default,,0000,0000,0000,,and in patients that were\Nhighly emotionally stable,
Dialogue: 0,0:04:24.22,0:04:28.12,Default,,0000,0000,0000,,which is of course the exact opposite\Nof how we use it as an antidepressant.
Dialogue: 0,0:04:28.14,0:04:32.60,Default,,0000,0000,0000,,They were so used to looking at it\Nfrom the perspective of this one disease,
Dialogue: 0,0:04:32.62,0:04:36.54,Default,,0000,0000,0000,,they could not see the larger implications\Nfor another disease.
Dialogue: 0,0:04:37.38,0:04:40.08,Default,,0000,0000,0000,,And to be fair,\Nit's not entirely their fault.
Dialogue: 0,0:04:40.10,0:04:42.88,Default,,0000,0000,0000,,Functional fixedness\Nis a bias that affects all of us.
Dialogue: 0,0:04:42.90,0:04:46.36,Default,,0000,0000,0000,,It's a tendency to only\Nbe able to think of an object
Dialogue: 0,0:04:46.38,0:04:48.98,Default,,0000,0000,0000,,in terms of its traditional\Nuse or function.
Dialogue: 0,0:04:49.74,0:04:51.64,Default,,0000,0000,0000,,And mental set is another thing. Right?
Dialogue: 0,0:04:51.66,0:04:53.68,Default,,0000,0000,0000,,That's sort of this preconceived framework
Dialogue: 0,0:04:53.70,0:04:55.48,Default,,0000,0000,0000,,with which we approach problems.
Dialogue: 0,0:04:55.50,0:04:58.76,Default,,0000,0000,0000,,And that actually makes repurposing\Npretty hard for all of us,
Dialogue: 0,0:04:58.78,0:05:02.32,Default,,0000,0000,0000,,which is, I guess, why they gave\Na TV show to the guy who was,
Dialogue: 0,0:05:02.34,0:05:04.14,Default,,0000,0000,0000,,like, really great at repurposing.
Dialogue: 0,0:05:04.66,0:05:06.54,Default,,0000,0000,0000,,(Laughter)
Dialogue: 0,0:05:07.18,0:05:11.52,Default,,0000,0000,0000,,So the effects in both the case\Nof iproniazid and imipramine,
Dialogue: 0,0:05:11.54,0:05:12.92,Default,,0000,0000,0000,,they were so strong --
Dialogue: 0,0:05:12.94,0:05:15.16,Default,,0000,0000,0000,,there was mania,\Nor people dancing in the halls.
Dialogue: 0,0:05:15.18,0:05:18.32,Default,,0000,0000,0000,,It's actually not that surprising\Nthey were caught.
Dialogue: 0,0:05:18.34,0:05:21.82,Default,,0000,0000,0000,,But it does make you wonder\Nwhat else we've missed.
Dialogue: 0,0:05:23.02,0:05:25.20,Default,,0000,0000,0000,,So iproniazid and imipramine,
Dialogue: 0,0:05:25.22,0:05:27.64,Default,,0000,0000,0000,,they're more than just\Na case study in repurposing.
Dialogue: 0,0:05:27.66,0:05:30.64,Default,,0000,0000,0000,,They have two other things in common\Nthat are really important.
Dialogue: 0,0:05:30.66,0:05:33.16,Default,,0000,0000,0000,,One, they have terrible side effects.
Dialogue: 0,0:05:33.18,0:05:35.80,Default,,0000,0000,0000,,That includes liver toxicity,
Dialogue: 0,0:05:35.82,0:05:38.80,Default,,0000,0000,0000,,weight gain of over 50 pounds,
Dialogue: 0,0:05:38.82,0:05:40.60,Default,,0000,0000,0000,,suicidality.
Dialogue: 0,0:05:40.62,0:05:44.80,Default,,0000,0000,0000,,And two, they both\Nincrease levels of serotonin,
Dialogue: 0,0:05:44.82,0:05:47.16,Default,,0000,0000,0000,,which is a chemical signal in the brain,
Dialogue: 0,0:05:47.18,0:05:48.38,Default,,0000,0000,0000,,or a neurotransmitter.
Dialogue: 0,0:05:49.38,0:05:51.88,Default,,0000,0000,0000,,And those two things together,\Nright, one or the two,
Dialogue: 0,0:05:51.90,0:05:53.52,Default,,0000,0000,0000,,may not have been that important,
Dialogue: 0,0:05:53.54,0:05:57.28,Default,,0000,0000,0000,,but the two together meant\Nthat we had to develop safer drugs,
Dialogue: 0,0:05:57.30,0:06:00.82,Default,,0000,0000,0000,,and that serotonin seemed\Nlike a pretty good place to start.
Dialogue: 0,0:06:01.66,0:06:05.56,Default,,0000,0000,0000,,So we developed drugs\Nto more specifically focus on serotonin,
Dialogue: 0,0:06:05.58,0:06:09.24,Default,,0000,0000,0000,,the selective serotonin\Nreuptake inhibitors, so the SSRIs,
Dialogue: 0,0:06:09.26,0:06:11.100,Default,,0000,0000,0000,,the most famous of which is Prozac.
Dialogue: 0,0:06:12.02,0:06:13.100,Default,,0000,0000,0000,,And that was 30 years ago,
Dialogue: 0,0:06:14.02,0:06:17.22,Default,,0000,0000,0000,,and since then we have mostly\Njust worked on optimizing those drugs.
Dialogue: 0,0:06:17.74,0:06:20.96,Default,,0000,0000,0000,,And the SSRIs, they are better\Nthan the drugs that came before them,
Dialogue: 0,0:06:20.98,0:06:23.08,Default,,0000,0000,0000,,but they still have a lot of side effects,
Dialogue: 0,0:06:23.10,0:06:25.100,Default,,0000,0000,0000,,including weight gain, insomnia,
Dialogue: 0,0:06:26.02,0:06:27.22,Default,,0000,0000,0000,,suicidality --
Dialogue: 0,0:06:28.10,0:06:30.44,Default,,0000,0000,0000,,and they take a really long time to work,
Dialogue: 0,0:06:30.46,0:06:32.100,Default,,0000,0000,0000,,something like four to six weeks\Nin a lot of patients.
Dialogue: 0,0:06:33.02,0:06:35.20,Default,,0000,0000,0000,,And that's in the patients\Nwhere they do work.
Dialogue: 0,0:06:35.22,0:06:38.08,Default,,0000,0000,0000,,There are a lot of patients\Nwhere these drugs don't work.
Dialogue: 0,0:06:38.10,0:06:41.48,Default,,0000,0000,0000,,And that means now, in 2016,
Dialogue: 0,0:06:41.50,0:06:45.32,Default,,0000,0000,0000,,we still have no cures\Nfor any mood disorders,
Dialogue: 0,0:06:45.34,0:06:47.40,Default,,0000,0000,0000,,just drugs that suppress symptoms,
Dialogue: 0,0:06:47.42,0:06:51.48,Default,,0000,0000,0000,,which is kind of the difference between\Ntaking a painkiller for an infection
Dialogue: 0,0:06:51.50,0:06:52.92,Default,,0000,0000,0000,,versus an antibiotic.
Dialogue: 0,0:06:52.94,0:06:54.80,Default,,0000,0000,0000,,A painkiller will make you feel better,
Dialogue: 0,0:06:54.82,0:06:57.90,Default,,0000,0000,0000,,but is not going to do anything\Nto treat that underlying disease.
Dialogue: 0,0:06:58.70,0:07:01.04,Default,,0000,0000,0000,,And it was this flexibility\Nin our thinking
Dialogue: 0,0:07:01.06,0:07:03.100,Default,,0000,0000,0000,,that let us recognize\Nthat iproniazid and imipramine
Dialogue: 0,0:07:04.02,0:07:06.12,Default,,0000,0000,0000,,could be repurposed in this way,
Dialogue: 0,0:07:06.14,0:07:08.12,Default,,0000,0000,0000,,which led us to the serotonin hypothesis,
Dialogue: 0,0:07:08.14,0:07:11.14,Default,,0000,0000,0000,,which we then, ironically, fixated on.
Dialogue: 0,0:07:11.98,0:07:14.52,Default,,0000,0000,0000,,This is brain signaling, serotonin,
Dialogue: 0,0:07:14.54,0:07:15.80,Default,,0000,0000,0000,,from an SSRI commercial.
Dialogue: 0,0:07:15.82,0:07:18.18,Default,,0000,0000,0000,,In case you're not clear,\Nthis is a dramatization.
Dialogue: 0,0:07:18.66,0:07:22.72,Default,,0000,0000,0000,,And in science, we try\Nand remove our bias, right,
Dialogue: 0,0:07:22.74,0:07:25.12,Default,,0000,0000,0000,,by running double-blinded experiments
Dialogue: 0,0:07:25.14,0:07:28.84,Default,,0000,0000,0000,,or being statistically agnostic\Nas to what our results will be.
Dialogue: 0,0:07:28.86,0:07:33.16,Default,,0000,0000,0000,,But bias creeps in more insidiously\Nin what we choose to study
Dialogue: 0,0:07:33.18,0:07:34.90,Default,,0000,0000,0000,,and how we choose to study it.
Dialogue: 0,0:07:36.26,0:07:39.84,Default,,0000,0000,0000,,So we've focused on serotonin now\Nfor the past 30 years,
Dialogue: 0,0:07:39.86,0:07:42.10,Default,,0000,0000,0000,,often to the exclusion of other things.
Dialogue: 0,0:07:42.86,0:07:44.22,Default,,0000,0000,0000,,We still have no cures,
Dialogue: 0,0:07:45.18,0:07:48.60,Default,,0000,0000,0000,,and what if serotonin\Nisn't all there is to depression?
Dialogue: 0,0:07:48.62,0:07:50.68,Default,,0000,0000,0000,,What if it's not even the key part of it?
Dialogue: 0,0:07:50.70,0:07:52.88,Default,,0000,0000,0000,,That means no matter how much time
Dialogue: 0,0:07:52.90,0:07:55.64,Default,,0000,0000,0000,,or money or effort we put into it,
Dialogue: 0,0:07:55.66,0:07:57.58,Default,,0000,0000,0000,,it will never lead to a cure.
Dialogue: 0,0:07:58.50,0:08:01.08,Default,,0000,0000,0000,,In the past few years,\Ndoctors have discovered
Dialogue: 0,0:08:01.10,0:08:06.02,Default,,0000,0000,0000,,probably what is the first truly new\Nantidepressant since the SSRIs,
Dialogue: 0,0:08:06.54,0:08:07.84,Default,,0000,0000,0000,,Calypsol,
Dialogue: 0,0:08:07.86,0:08:11.32,Default,,0000,0000,0000,,and this drug works very quickly,\Nwithin a few hours or a day,
Dialogue: 0,0:08:11.34,0:08:13.24,Default,,0000,0000,0000,,and it doesn't work on serotonin.
Dialogue: 0,0:08:13.26,0:08:15.94,Default,,0000,0000,0000,,It works on glutamate,\Nwhich is another neurotransmitter.
Dialogue: 0,0:08:16.38,0:08:17.88,Default,,0000,0000,0000,,And it's also repurposed.
Dialogue: 0,0:08:17.90,0:08:20.98,Default,,0000,0000,0000,,It was traditionally used\Nas anesthesia in surgery.
Dialogue: 0,0:08:21.54,0:08:23.20,Default,,0000,0000,0000,,But unlike those other drugs,
Dialogue: 0,0:08:23.22,0:08:25.04,Default,,0000,0000,0000,,which were recognized pretty quickly,
Dialogue: 0,0:08:25.06,0:08:26.76,Default,,0000,0000,0000,,it took us 20 years
Dialogue: 0,0:08:26.78,0:08:29.44,Default,,0000,0000,0000,,to realize that Calypsol\Nwas an antidepressant,
Dialogue: 0,0:08:29.46,0:08:32.32,Default,,0000,0000,0000,,despite the fact that it's actually\Na better antidepressant,
Dialogue: 0,0:08:32.34,0:08:33.96,Default,,0000,0000,0000,,probably, than those other drugs.
Dialogue: 0,0:08:33.98,0:08:38.08,Default,,0000,0000,0000,,It's actually probably because of the fact\Nthat it's a better antidepressant
Dialogue: 0,0:08:38.10,0:08:39.100,Default,,0000,0000,0000,,that it was harder for us to recognize.
Dialogue: 0,0:08:40.02,0:08:42.10,Default,,0000,0000,0000,,There was no mania to signal its effects.
Dialogue: 0,0:08:42.58,0:08:45.68,Default,,0000,0000,0000,,So in 2013, up at Columbia University,
Dialogue: 0,0:08:45.70,0:08:47.28,Default,,0000,0000,0000,,I was working with my colleague,
Dialogue: 0,0:08:47.30,0:08:49.28,Default,,0000,0000,0000,,Dr. Christine Ann Denny,
Dialogue: 0,0:08:49.30,0:08:53.10,Default,,0000,0000,0000,,and we were studying Calypsol\Nas an antidepressant in mice.
Dialogue: 0,0:08:53.66,0:08:56.48,Default,,0000,0000,0000,,And Calypsol has, like,\Na really short half-life,
Dialogue: 0,0:08:56.50,0:08:59.56,Default,,0000,0000,0000,,which means it's out of your body\Nwithin a few hours.
Dialogue: 0,0:08:59.58,0:09:00.100,Default,,0000,0000,0000,,And we were just piloting.
Dialogue: 0,0:09:01.02,0:09:03.28,Default,,0000,0000,0000,,So we would give an injection to mice,
Dialogue: 0,0:09:03.30,0:09:04.60,Default,,0000,0000,0000,,and then we'd wait a week,
Dialogue: 0,0:09:04.62,0:09:07.30,Default,,0000,0000,0000,,and then we'd run\Nanother experiment to save money.
Dialogue: 0,0:09:08.02,0:09:10.16,Default,,0000,0000,0000,,And one of the experiments I was running,
Dialogue: 0,0:09:10.18,0:09:11.84,Default,,0000,0000,0000,,we would stress the mice,
Dialogue: 0,0:09:11.86,0:09:14.08,Default,,0000,0000,0000,,and we used that as a model of depression.
Dialogue: 0,0:09:14.10,0:09:17.44,Default,,0000,0000,0000,,And at first it kind of just looked\Nlike it didn't really work at all.
Dialogue: 0,0:09:17.46,0:09:18.98,Default,,0000,0000,0000,,So we could have stopped there.
Dialogue: 0,0:09:19.54,0:09:22.44,Default,,0000,0000,0000,,But I have run this model\Nof depression for years,
Dialogue: 0,0:09:22.46,0:09:24.36,Default,,0000,0000,0000,,and the data just looked kind of weird.
Dialogue: 0,0:09:24.38,0:09:26.24,Default,,0000,0000,0000,,It didn't really look right to me.
Dialogue: 0,0:09:26.26,0:09:27.48,Default,,0000,0000,0000,,So I went back,
Dialogue: 0,0:09:27.50,0:09:28.100,Default,,0000,0000,0000,,and we reanalyzed it
Dialogue: 0,0:09:29.02,0:09:32.84,Default,,0000,0000,0000,,based on whether or not they had gotten\Nthat one injection of Calypsol
Dialogue: 0,0:09:32.86,0:09:34.06,Default,,0000,0000,0000,,a week beforehand.
Dialogue: 0,0:09:34.94,0:09:36.96,Default,,0000,0000,0000,,And it looked kind of like this.
Dialogue: 0,0:09:36.98,0:09:39.12,Default,,0000,0000,0000,,So if you look at the far left,
Dialogue: 0,0:09:39.14,0:09:41.64,Default,,0000,0000,0000,,if you put a mouse in a new space,
Dialogue: 0,0:09:41.66,0:09:43.92,Default,,0000,0000,0000,,this is the box, it's very exciting,
Dialogue: 0,0:09:43.94,0:09:46.08,Default,,0000,0000,0000,,a mouse will walk around and explore,
Dialogue: 0,0:09:46.10,0:09:50.40,Default,,0000,0000,0000,,and you can see that pink line\Nis actually the measure of them walking.
Dialogue: 0,0:09:50.42,0:09:53.60,Default,,0000,0000,0000,,And we also give it\Nanother mouse in a pencil cup
Dialogue: 0,0:09:53.62,0:09:55.68,Default,,0000,0000,0000,,that it can decide to interact with.
Dialogue: 0,0:09:55.70,0:09:58.92,Default,,0000,0000,0000,,This is also a dramatization,\Nin case that's not clear.
Dialogue: 0,0:09:58.94,0:10:02.64,Default,,0000,0000,0000,,And a normal mouse will explore.
Dialogue: 0,0:10:02.66,0:10:03.90,Default,,0000,0000,0000,,It will be social.
Dialogue: 0,0:10:04.62,0:10:05.100,Default,,0000,0000,0000,,Check out what's going on.
Dialogue: 0,0:10:06.02,0:10:08.92,Default,,0000,0000,0000,,If you stress a mouse\Nin this depression model,
Dialogue: 0,0:10:08.94,0:10:10.22,Default,,0000,0000,0000,,which is the middle box,
Dialogue: 0,0:10:11.10,0:10:12.100,Default,,0000,0000,0000,,they aren't social, they don't explore.
Dialogue: 0,0:10:13.02,0:10:16.30,Default,,0000,0000,0000,,They mostly just kind of hide\Nin that back corner, behind a cup.
Dialogue: 0,0:10:17.02,0:10:20.12,Default,,0000,0000,0000,,Yet the mice that had gotten\Nthat one injection of Calypsol,
Dialogue: 0,0:10:20.14,0:10:21.34,Default,,0000,0000,0000,,here on your right,
Dialogue: 0,0:10:22.06,0:10:24.02,Default,,0000,0000,0000,,they were exploring, they were social.
Dialogue: 0,0:10:24.74,0:10:27.22,Default,,0000,0000,0000,,They looked like they\Nhad never been stressed at all,
Dialogue: 0,0:10:28.02,0:10:29.22,Default,,0000,0000,0000,,which is impossible.
Dialogue: 0,0:10:30.26,0:10:31.98,Default,,0000,0000,0000,,So we could have just stopped there,
Dialogue: 0,0:10:32.78,0:10:37.08,Default,,0000,0000,0000,,but Christine had also used\NCalypsol before as anesthesia,
Dialogue: 0,0:10:37.10,0:10:38.68,Default,,0000,0000,0000,,and a few years ago she had seen
Dialogue: 0,0:10:38.70,0:10:41.08,Default,,0000,0000,0000,,that it seemed to have\Nsome weird effects on cells
Dialogue: 0,0:10:41.10,0:10:42.32,Default,,0000,0000,0000,,and some other behavior
Dialogue: 0,0:10:42.34,0:10:45.36,Default,,0000,0000,0000,,that also seemed to last\Nlong after the drug,
Dialogue: 0,0:10:45.38,0:10:46.64,Default,,0000,0000,0000,,maybe a few weeks.
Dialogue: 0,0:10:46.66,0:10:47.92,Default,,0000,0000,0000,,So we were like, OK,
Dialogue: 0,0:10:47.94,0:10:50.12,Default,,0000,0000,0000,,maybe this is not completely impossible,
Dialogue: 0,0:10:50.14,0:10:51.64,Default,,0000,0000,0000,,but we were really skeptical.
Dialogue: 0,0:10:51.66,0:10:54.20,Default,,0000,0000,0000,,So we did what you do in science\Nwhen you're not sure,
Dialogue: 0,0:10:54.22,0:10:55.42,Default,,0000,0000,0000,,and we ran it again.
Dialogue: 0,0:10:56.46,0:10:59.48,Default,,0000,0000,0000,,And I remember being in the animal room,
Dialogue: 0,0:10:59.50,0:11:03.16,Default,,0000,0000,0000,,moving mice from box to box\Nto test them,
Dialogue: 0,0:11:03.18,0:11:06.80,Default,,0000,0000,0000,,and Christine was actually sitting\Non the floor with the computer in her lap
Dialogue: 0,0:11:06.82,0:11:08.24,Default,,0000,0000,0000,,so the mice couldn't see her,
Dialogue: 0,0:11:08.26,0:11:10.52,Default,,0000,0000,0000,,and she was analyzing\Nthe data in real time.
Dialogue: 0,0:11:10.54,0:11:11.92,Default,,0000,0000,0000,,And I remember us yelling,
Dialogue: 0,0:11:11.94,0:11:15.24,Default,,0000,0000,0000,,which you're not supposed to do\Nin an animal room where you're testing,
Dialogue: 0,0:11:15.26,0:11:16.84,Default,,0000,0000,0000,,because it had worked.
Dialogue: 0,0:11:16.86,0:11:21.24,Default,,0000,0000,0000,,It seemed like these mice\Nwere protected against stress,
Dialogue: 0,0:11:21.26,0:11:24.32,Default,,0000,0000,0000,,or they were inappropriately happy,\Nhowever you want to call it.
Dialogue: 0,0:11:24.34,0:11:26.78,Default,,0000,0000,0000,,And we were really excited.
Dialogue: 0,0:11:27.82,0:11:31.30,Default,,0000,0000,0000,,And then we were really skeptical,\Nbecause it was too good to be true.
Dialogue: 0,0:11:31.86,0:11:33.06,Default,,0000,0000,0000,,So we ran it again.
Dialogue: 0,0:11:33.74,0:11:36.48,Default,,0000,0000,0000,,And then we ran it again in a PTSD model,
Dialogue: 0,0:11:36.50,0:11:38.92,Default,,0000,0000,0000,,and we ran it again\Nin a physiological model,
Dialogue: 0,0:11:38.94,0:11:41.16,Default,,0000,0000,0000,,where all we did was give stress hormones.
Dialogue: 0,0:11:41.18,0:11:42.80,Default,,0000,0000,0000,,And we had our undergrads run it.
Dialogue: 0,0:11:42.82,0:11:46.94,Default,,0000,0000,0000,,And then we had our collaborators\Nhalfway across the world in France run it.
Dialogue: 0,0:11:47.78,0:11:50.100,Default,,0000,0000,0000,,And every time someone ran it,\Nthey confirmed the same thing.
Dialogue: 0,0:11:51.02,0:11:53.84,Default,,0000,0000,0000,,It seemed like\Nthis one injection of Calypsol
Dialogue: 0,0:11:53.86,0:11:56.62,Default,,0000,0000,0000,,was somehow protecting\Nagainst stress for weeks.
Dialogue: 0,0:11:57.18,0:11:59.04,Default,,0000,0000,0000,,And we only published this a year ago,
Dialogue: 0,0:11:59.06,0:12:03.14,Default,,0000,0000,0000,,but since then other labs\Nhave independently confirmed this effect.
Dialogue: 0,0:12:03.94,0:12:05.86,Default,,0000,0000,0000,,So we don't know what causes depression,
Dialogue: 0,0:12:06.46,0:12:10.16,Default,,0000,0000,0000,,but we do know that stress\Nis the initial trigger
Dialogue: 0,0:12:10.18,0:12:12.52,Default,,0000,0000,0000,,in 80 percent of cases,
Dialogue: 0,0:12:12.54,0:12:14.76,Default,,0000,0000,0000,,and depression and PTSD\Nare different diseases,
Dialogue: 0,0:12:14.78,0:12:16.80,Default,,0000,0000,0000,,but this is something\Nthey share in common.
Dialogue: 0,0:12:16.82,0:12:18.64,Default,,0000,0000,0000,,Right? It is traumatic stress
Dialogue: 0,0:12:18.66,0:12:21.56,Default,,0000,0000,0000,,like active combat or natural disasters
Dialogue: 0,0:12:21.58,0:12:24.04,Default,,0000,0000,0000,,or community violence or sexual assault
Dialogue: 0,0:12:24.06,0:12:26.34,Default,,0000,0000,0000,,that causes post-traumatic\Nstress disorder,
Dialogue: 0,0:12:26.98,0:12:32.60,Default,,0000,0000,0000,,and not everyone that is exposed to stress\Ndevelops a mood disorder.
Dialogue: 0,0:12:32.62,0:12:35.52,Default,,0000,0000,0000,,And this ability to experience\Nstress and be resilient
Dialogue: 0,0:12:35.54,0:12:39.70,Default,,0000,0000,0000,,and bounce back and not develop\Ndepression or PTSD
Dialogue: 0,0:12:40.50,0:12:42.76,Default,,0000,0000,0000,,is known as stress resilience,
Dialogue: 0,0:12:42.78,0:12:44.64,Default,,0000,0000,0000,,and it varies between people.
Dialogue: 0,0:12:44.66,0:12:47.100,Default,,0000,0000,0000,,And we have always thought of it\Nas just sort of this passive property.
Dialogue: 0,0:12:48.02,0:12:50.56,Default,,0000,0000,0000,,It's the absence of susceptibility factors
Dialogue: 0,0:12:50.58,0:12:52.66,Default,,0000,0000,0000,,and risk factors for these disorders.
Dialogue: 0,0:12:53.62,0:12:55.50,Default,,0000,0000,0000,,But what if it were active?
Dialogue: 0,0:12:56.42,0:12:57.92,Default,,0000,0000,0000,,Maybe we could enhance it,
Dialogue: 0,0:12:57.94,0:13:00.10,Default,,0000,0000,0000,,sort of akin to putting on armor.
Dialogue: 0,0:13:01.22,0:13:05.82,Default,,0000,0000,0000,,We had accidentally discovered\Nthe first resilience-enhancing drug.
Dialogue: 0,0:13:06.74,0:13:09.52,Default,,0000,0000,0000,,And like I said, we only gave\Na tiny amount of the drug,
Dialogue: 0,0:13:09.54,0:13:11.12,Default,,0000,0000,0000,,and it lasted for weeks,
Dialogue: 0,0:13:11.14,0:13:14.36,Default,,0000,0000,0000,,and that's not like anything\Nyou see with antidepressants.
Dialogue: 0,0:13:14.38,0:13:18.70,Default,,0000,0000,0000,,But it is actually kind of similar\Nto what you see in immune vaccines.
Dialogue: 0,0:13:19.18,0:13:22.12,Default,,0000,0000,0000,,So in immune vaccines,\Nyou'll get your shots,
Dialogue: 0,0:13:22.14,0:13:25.52,Default,,0000,0000,0000,,and then weeks, months, years later,
Dialogue: 0,0:13:25.54,0:13:27.88,Default,,0000,0000,0000,,when you're actually exposed to bacteria,
Dialogue: 0,0:13:27.90,0:13:30.36,Default,,0000,0000,0000,,it's not the vaccine in your body\Nthat protects you.
Dialogue: 0,0:13:30.38,0:13:31.76,Default,,0000,0000,0000,,It's your own immune system
Dialogue: 0,0:13:31.78,0:13:35.92,Default,,0000,0000,0000,,that's developed resistance and resilience\Nto this bacteria that fights it off,
Dialogue: 0,0:13:35.94,0:13:38.08,Default,,0000,0000,0000,,and you actually never get the infection,
Dialogue: 0,0:13:38.10,0:13:41.16,Default,,0000,0000,0000,,which is very different\Nfrom, say, our treatments. Right?
Dialogue: 0,0:13:41.18,0:13:44.100,Default,,0000,0000,0000,,In that case, you get the infection,\Nyou're exposed to the bacteria,
Dialogue: 0,0:13:45.02,0:13:48.88,Default,,0000,0000,0000,,you're sick, and then you take,\Nsay, an antibiotic which cures it,
Dialogue: 0,0:13:48.90,0:13:52.14,Default,,0000,0000,0000,,and those drugs are actually working\Nto kill the bacteria.
Dialogue: 0,0:13:52.78,0:13:55.28,Default,,0000,0000,0000,,Or similar to as I said before,\Nwith this palliative,
Dialogue: 0,0:13:55.30,0:13:58.16,Default,,0000,0000,0000,,you'll take something\Nthat will suppress the symptoms,
Dialogue: 0,0:13:58.18,0:14:00.88,Default,,0000,0000,0000,,but it won't treat\Nthe underlying infection,
Dialogue: 0,0:14:00.90,0:14:04.24,Default,,0000,0000,0000,,and you'll only feel better\Nduring the time in which you're taking it,
Dialogue: 0,0:14:04.26,0:14:06.20,Default,,0000,0000,0000,,which is why you have to keep taking it.
Dialogue: 0,0:14:06.22,0:14:08.92,Default,,0000,0000,0000,,And in depression and PTSD --
Dialogue: 0,0:14:08.94,0:14:10.92,Default,,0000,0000,0000,,here we have your stress exposure --
Dialogue: 0,0:14:10.94,0:14:13.56,Default,,0000,0000,0000,,we only have palliative care.
Dialogue: 0,0:14:13.58,0:14:16.08,Default,,0000,0000,0000,,Antidepressants only suppress symptoms,
Dialogue: 0,0:14:16.10,0:14:18.96,Default,,0000,0000,0000,,and that is why you basically\Nhave to keep taking them
Dialogue: 0,0:14:18.98,0:14:20.68,Default,,0000,0000,0000,,for the life of the disease,
Dialogue: 0,0:14:20.70,0:14:22.90,Default,,0000,0000,0000,,which is often\Nthe length of your own life.
Dialogue: 0,0:14:23.94,0:14:28.16,Default,,0000,0000,0000,,So we're calling our resilience-enhancing\Ndrugs "paravaccines,"
Dialogue: 0,0:14:28.18,0:14:29.72,Default,,0000,0000,0000,,which means vaccine-like,
Dialogue: 0,0:14:29.74,0:14:32.24,Default,,0000,0000,0000,,because it seems\Nlike they might have the potential
Dialogue: 0,0:14:32.26,0:14:34.08,Default,,0000,0000,0000,,to protect against stress
Dialogue: 0,0:14:34.10,0:14:37.52,Default,,0000,0000,0000,,and prevent mice from developing
Dialogue: 0,0:14:37.54,0:14:40.30,Default,,0000,0000,0000,,depression and post-traumatic\Nstress disorder.
Dialogue: 0,0:14:40.78,0:14:44.22,Default,,0000,0000,0000,,Also, not all antidepressants\Nare also paravaccines.
Dialogue: 0,0:14:45.30,0:14:46.92,Default,,0000,0000,0000,,We tried Prozac as well,
Dialogue: 0,0:14:46.94,0:14:48.30,Default,,0000,0000,0000,,and that had no effect.
Dialogue: 0,0:14:49.06,0:14:52.08,Default,,0000,0000,0000,,So if this were to translate into humans,
Dialogue: 0,0:14:52.10,0:14:54.68,Default,,0000,0000,0000,,we might be able to protect people
Dialogue: 0,0:14:54.70,0:14:56.96,Default,,0000,0000,0000,,who are predictably at risk
Dialogue: 0,0:14:56.98,0:15:00.84,Default,,0000,0000,0000,,against stress-induced disorders\Nlike depression and PTSD.
Dialogue: 0,0:15:00.86,0:15:03.100,Default,,0000,0000,0000,,So that's first responders\Nand firefighters,
Dialogue: 0,0:15:04.02,0:15:08.16,Default,,0000,0000,0000,,refugees, prisoners and prison guards,
Dialogue: 0,0:15:08.18,0:15:10.26,Default,,0000,0000,0000,,soldiers, you name it.
Dialogue: 0,0:15:11.22,0:15:15.02,Default,,0000,0000,0000,,And to give you a sense\Nof the scale of these diseases,
Dialogue: 0,0:15:15.62,0:15:18.68,Default,,0000,0000,0000,,in 2010, the global burden of disease
Dialogue: 0,0:15:18.70,0:15:22.54,Default,,0000,0000,0000,,was estimated at 2.5 trillion dollars,
Dialogue: 0,0:15:23.06,0:15:24.60,Default,,0000,0000,0000,,and since they are chronic,
Dialogue: 0,0:15:24.62,0:15:27.84,Default,,0000,0000,0000,,that cost is compounding\Nand is therefore expected to rise
Dialogue: 0,0:15:27.86,0:15:31.10,Default,,0000,0000,0000,,up to six trillion dollars\Nin just the next 15 years.
Dialogue: 0,0:15:32.46,0:15:34.04,Default,,0000,0000,0000,,As I mentioned before,
Dialogue: 0,0:15:34.06,0:15:38.14,Default,,0000,0000,0000,,repurposing can be challenging\Nbecause of our prior biases.
Dialogue: 0,0:15:38.86,0:15:40.38,Default,,0000,0000,0000,,Calypsol has another name,
Dialogue: 0,0:15:41.10,0:15:42.30,Default,,0000,0000,0000,,ketamine,
Dialogue: 0,0:15:43.38,0:15:44.94,Default,,0000,0000,0000,,which also goes by another name,
Dialogue: 0,0:15:45.46,0:15:46.88,Default,,0000,0000,0000,,Special K,
Dialogue: 0,0:15:46.90,0:15:49.30,Default,,0000,0000,0000,,which is a club drug and drug of abuse.
Dialogue: 0,0:15:50.54,0:15:53.64,Default,,0000,0000,0000,,It's still used across the world\Nas an anesthetic.
Dialogue: 0,0:15:53.66,0:15:56.52,Default,,0000,0000,0000,,It's used in children.\NWe use it on the battlefield.
Dialogue: 0,0:15:56.54,0:15:59.52,Default,,0000,0000,0000,,It's actually the drug of choice\Nin a lot of developing nations,
Dialogue: 0,0:15:59.54,0:16:01.40,Default,,0000,0000,0000,,because it doesn't affect breathing.
Dialogue: 0,0:16:01.42,0:16:06.10,Default,,0000,0000,0000,,It is on the World Health Organization\Nlist of most essential medicines.
Dialogue: 0,0:16:06.58,0:16:10.14,Default,,0000,0000,0000,,If we had discovered ketamine\Nas a paravaccine first,
Dialogue: 0,0:16:10.82,0:16:13.68,Default,,0000,0000,0000,,it'd be pretty easy for us to develop it,
Dialogue: 0,0:16:13.70,0:16:17.56,Default,,0000,0000,0000,,but as is, we have to compete\Nwith our functional fixedness
Dialogue: 0,0:16:17.58,0:16:20.38,Default,,0000,0000,0000,,and mental set that kind of interfere.
Dialogue: 0,0:16:21.70,0:16:25.56,Default,,0000,0000,0000,,Fortunately, it's not\Nthe only compound we have discovered
Dialogue: 0,0:16:25.58,0:16:29.02,Default,,0000,0000,0000,,that has these prophylactic,\Nparavaccine qualities,
Dialogue: 0,0:16:29.70,0:16:31.90,Default,,0000,0000,0000,,but all of the other drugs\Nwe've discovered,
Dialogue: 0,0:16:32.78,0:16:34.96,Default,,0000,0000,0000,,or compounds if you will,\Nthey're totally new,
Dialogue: 0,0:16:34.98,0:16:38.60,Default,,0000,0000,0000,,they have to go through\Nthe entire FDA approval process --
Dialogue: 0,0:16:38.62,0:16:42.20,Default,,0000,0000,0000,,if they make it before\Nthey can ever be used in humans.
Dialogue: 0,0:16:42.22,0:16:43.88,Default,,0000,0000,0000,,And that will be years.
Dialogue: 0,0:16:43.90,0:16:46.16,Default,,0000,0000,0000,,So if we wanted something sooner,
Dialogue: 0,0:16:46.18,0:16:48.56,Default,,0000,0000,0000,,ketamine is already FDA-approved.
Dialogue: 0,0:16:48.58,0:16:51.28,Default,,0000,0000,0000,,It's generic, it's available.
Dialogue: 0,0:16:51.30,0:16:55.46,Default,,0000,0000,0000,,We could develop it for a fraction\Nof the price and a fraction of the time.
Dialogue: 0,0:16:56.38,0:17:00.76,Default,,0000,0000,0000,,But actually, beyond\Nfunctional fixedness and mental set,
Dialogue: 0,0:17:00.78,0:17:04.36,Default,,0000,0000,0000,,there's a real other challenge\Nto repurposing drugs,
Dialogue: 0,0:17:04.38,0:17:05.58,Default,,0000,0000,0000,,which is policy.
Dialogue: 0,0:17:06.18,0:17:08.40,Default,,0000,0000,0000,,There are no incentives in place
Dialogue: 0,0:17:08.42,0:17:12.16,Default,,0000,0000,0000,,once a drug is generic and off patent\Nand no longer exclusive
Dialogue: 0,0:17:12.18,0:17:14.52,Default,,0000,0000,0000,,to encourage pharma companies\Nto develop them,
Dialogue: 0,0:17:14.54,0:17:15.97,Default,,0000,0000,0000,,because they don't make money.
Dialogue: 0,0:17:16.38,0:17:19.50,Default,,0000,0000,0000,,And that's not true for just ketamine.\NThat is true for all drugs.
Dialogue: 0,0:17:20.58,0:17:26.24,Default,,0000,0000,0000,,Regardless, the idea itself\Nis completely novel in psychiatry,
Dialogue: 0,0:17:26.26,0:17:30.16,Default,,0000,0000,0000,,to use drugs to prevent mental illness
Dialogue: 0,0:17:30.18,0:17:31.54,Default,,0000,0000,0000,,as opposed to just treat it.
Dialogue: 0,0:17:32.74,0:17:37.80,Default,,0000,0000,0000,,It is possible that 20, 50,\N100 years from now,
Dialogue: 0,0:17:37.82,0:17:41.92,Default,,0000,0000,0000,,we will look back now\Nat depression and PTSD
Dialogue: 0,0:17:41.94,0:17:45.16,Default,,0000,0000,0000,,the way we look back\Nat tuberculosis sanitoriums
Dialogue: 0,0:17:45.18,0:17:46.38,Default,,0000,0000,0000,,as a thing of the past.
Dialogue: 0,0:17:47.18,0:17:52.42,Default,,0000,0000,0000,,This could be the beginning of the end\Nof the mental health epidemic.
Dialogue: 0,0:17:53.38,0:17:56.58,Default,,0000,0000,0000,,But as a great scientist once said,
Dialogue: 0,0:17:57.90,0:18:00.16,Default,,0000,0000,0000,,"Only a fool is sure of anything.
Dialogue: 0,0:18:00.18,0:18:02.22,Default,,0000,0000,0000,,A wise man keeps on guessing."
Dialogue: 0,0:18:04.04,0:18:05.28,Default,,0000,0000,0000,,Thank you, guys.
Dialogue: 0,0:18:05.78,0:18:09.85,Default,,0000,0000,0000,,(Applause)